EP2750665A1 - Oral formulations containing hyaluronic acid for sustained drug release - Google Patents

Oral formulations containing hyaluronic acid for sustained drug release

Info

Publication number
EP2750665A1
EP2750665A1 EP12751545.0A EP12751545A EP2750665A1 EP 2750665 A1 EP2750665 A1 EP 2750665A1 EP 12751545 A EP12751545 A EP 12751545A EP 2750665 A1 EP2750665 A1 EP 2750665A1
Authority
EP
European Patent Office
Prior art keywords
tablet
capsule
hyaluronic acid
salt
hyaluronate
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12751545.0A
Other languages
German (de)
English (en)
French (fr)
Inventor
Ole Moeller DALL
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novozymes Biopharma DK AS
Original Assignee
Novozymes Biopharma DK AS
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Novozymes Biopharma DK AS filed Critical Novozymes Biopharma DK AS
Priority to EP12751545.0A priority Critical patent/EP2750665A1/en
Publication of EP2750665A1 publication Critical patent/EP2750665A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin

Definitions

  • the present invention relates to sustained-release oral formulations comprising an active pharmaceutical ingredient, hyaluronic acid or a salt thereof, and a coating.
  • the invention also relates to methods for producing these oral formulations, and to the use of these oral formulations in the manufacture of a medicament for the treatment of various diseases.
  • Controlled-release is a mechanism used in tablets or capsules whereby the tablets or the capsules are dissolved slowly releasing a drug over time.
  • sustained-release tablets or capsules are that they can often be taken less frequently than immediate-release formulations of the same drug, and that they keep steadier levels of the drug in the bloodstream.
  • time-release drugs are formulated so that the active ingredient is embedded in a matrix of insoluble substance(s) (e.g., cellulose derivates and/or acrylics) in such a way that the dissolving drug must find its way out through the holes in the matrix.
  • insoluble substance(s) e.g., cellulose derivates and/or acrylics
  • the drug dissolves into the matrix, and the matrix physically swells to form a gel, allowing the drug to exit through the outer surface of the gel.
  • Hyaluronic acid is a natural and linear carbohydrate polymer belonging to the class of non-sulfated glycosaminoglycans. It is composed of beta-1 ,3-/V-acetyl glucosamine and beta-1 ,4-glucuronic acid repeating disaccharide units with a molecular weight (MW) up to 6 MDa. HA is present in hyaline cartilage, synovial joint fluid, and skin tissue, both dermis and epidermis.
  • HA Due to the unique physical and biological properties of HA (including biocompatibility and biodegradability), HA is employed in a wide range of current and developing applications.
  • WO 03/061626 discloses an injectable, insertable or implantable drug delivery system that form hydrogels when implanted, injected or inserted comprising hyaluronic acid and a pharmaceutically effective compound.
  • WO 97/28828 discloses a pharmaceutical composition comprising an effective amount of a controlled release polymer and a proteinaceous interleukin-1 inhibitor.
  • EP 0913149 discloses a drug composition with a controlled drug release rate comprising a high-molecular substance and/or polyvalent metal ions, hyaluronic acid, and a drug.
  • US 2005/0031546 discloses an abuse-proofed dosage form comprising an active ingredient and a synthetic or natural polymer with a breaking strength of at least 500 N.
  • an active pharmaceutical ingredient and hyaluronic acid may be formulated into a slow release tablet or capsule for oral administration so we claim:
  • a tablet or a capsule comprising a) 0.5 - 50 % (w/w) hyaluronic acid or a salt thereof, b) an active pharmaceutical ingredient (API), and c) a coating for use in oral administration.
  • API active pharmaceutical ingredient
  • the present invention also claims a method of producing a tablet or a capsule comprising a) mixing hyaluronic acid or a salt thereof with an active pharmaceutical ingredient (API); b) granulating the mixture from step a) into pellets; c) compressing the pellets into a tablet or filling the pellets into a capsule; and d) coating the tablet or the capsule.
  • API active pharmaceutical ingredient
  • the present invention also claims a method of producing a capsule comprising
  • the present invention also claims a tablet or a capsule comprising a) 0.5 - 50 % (w/w) hyaluronic acid or a salt thereof, b) an active pharmaceutical ingredient (API), and c) a coating, for the manufacture of a medicament for use in the treatment of pain, migraine, epilepsy, anxious disorders, inflammatory conditions, infectious diseases, hormonal disorders, cardiovascular diseases, gastro intestinal illnesses or cancer.
  • the present invention discloses a tablet or a capsule for oral administration comprising 0.5 - 50 % (w/w) hyaluronic acid or a salt thereof, an active pharmaceutical ingredient (API), and a coating.
  • HA's role in this invention is to increase the viscosity and/or to form a high viscous gel-like core in the tablet or the capsule in order to slow down the release of the API.
  • Hyaluronic acid is defined herein as an unsulphated glycosaminoglycan composed of repeating disaccharide units of N-acetylglucosamine (GlcNAc) and glucuronic acid (GlcUA) linked together by alternating beta-1 ,4 and beta-1 ,3 glycosidic bonds.
  • Hyaluronic acid is also known as hyaluronan, hyaluronate, or HA.
  • the terms hyaluronan, hyaluronic acid, and HA are used interchangeably herein.
  • the level of hyaluronic acid may be determined according to the modified carbazole method (Bitter and Muir, 1962, Anal Biochem. 4: 330-334).
  • the hyaluronic acid used according to the invention is of a very pure quality, in particular cGMP.
  • Rooster combs are a significant commercial source for hyaluronan. Microorganisms are an alternative source.
  • US 4,801 ,539 and EP 0694616 disclose fermentation methods for preparing hyaluronic acid involving a strain of Streptococcus zooepidemicus.
  • the hyaluronic acid or salt thereof is of microbial origin, preferably recombinantly produced.
  • the hyaluronic acid or salt thereof is produced by a Gram-positive bacterium such as Bacillus.
  • the hyaluronic acid or salt thereof is produced by Bacillus subtilis.
  • the hyaluronic acid or salt thereof may be produced as disclosed in WO 03/054163.
  • Hyaluronan synthases have been described from vertebrates, bacterial pathogens, and algal viruses (DeAngelis, P. L, 1999, Cell. Mol. Life Sci. 56: 670-682).
  • WO 99/23227 discloses a Group I hyaluronate synthase from Streptococcus equisimilis.
  • WO 99/51265 and WO 00/27437 describe a Group II hyaluronate synthase from Pasturella multocida. Ferretti et al.
  • WO 99/51265 describes a nucleic acid segment having a coding region for a Streptococcus equisimilis hyaluronan synthase.
  • the host cell may be any Bacillus cell suitable for recombinant production of hyaluronic acid.
  • the Bacillus host cell may be a wild-type Bacillus cell or a mutant thereof.
  • Bacillus cells useful in the practice of the present invention include, but are not limited to, Bacillus agaraderhens, Bacillus alkalophilus, Bacillus amyloliquefaciens, Bacillus brevis, Bacillus circulans, Bacillus clausii, Bacillus coagulans, Bacillus firmus, Bacillus lautus, Bacillus lentus, Bacillus licheniformis, Bacillus megaterium, Bacillus pumilus, Bacillus stearothermophilus, Bacillus subtilis, and Bacillus thuringiensis cells. Mutant Bacillus subtilis cells particularly adapted for recombinant expression are described in WO 98/22598. Non- encapsulating Bacillus cells are particularly useful in the present invention.
  • the hyaluronan of a recombinant Bacillus cell is expressed directly to the culture medium, a simple process may be used to isolate the hyaluronan from the culture medium.
  • the culture medium may be diluted first, if desired, to reduce the viscosity of the medium.
  • Many methods are known to those skilled in the art for removing cells from culture medium, such as centrifugation or microfiltration.
  • the remaining supernatant may then be filtered, such as by ultrafiltration, to concentrate and remove small molecule contaminants from the hyaluronan.
  • Various purification steps may then be performed depending on the required purity of the final product.
  • the hyaluronan may be dried or concentrated by using evaporative techniques known to the person skilled in the art, such as lyophilization or spray drying. Salts of hyaluronic acid
  • Any salt of hyaluronic acid may be used according to the present invention.
  • the salt of hyaluronic acid is an inorganic salt, preferably sodium hyaluronate, potassium hyaluronate, ammonium hyaluronate, calcium hyaluronate, magnesium hyaluronate, zinc hyaluronate, or cobalt hyaluronate.
  • the hyaluronic acid or the salt thereof has an average molecular weight in the range of 200-6000 kDa; more preferably an average molecular weight in the range of 300- 6000 kDa; more preferably an average molecular weight in the range of 400-6000 kDa; and even more preferably an average molecular weight in the range of 500-6000 kDa.
  • the molecular weight may be determined as known in the art.
  • the active pharmaceutical ingredient of interest may be any compound known in the art suitable for oral administration, e.g., a peptide, a protein, an enzyme, a hormone, an antibiotic, a fungicide or an analgesic.
  • the active pharmaceutical ingredient is an analgesic (also known as a painkiller).
  • An analgesic is any member of the group of drugs used to relieve pain (achieve analgesia).
  • Analgesic drugs act in various ways on the peripheral and central nervous systems; they include paracetamol (para-acetylaminophenol), the non-steroidal anti-inflammatory drugs (NSAIDs such as COX-1 and COX-2, selective and non-selective), and opioid drugs.
  • the opioid drugs may be of natural or synthetic origin, and analogs are included, e.g., morphine and opium.
  • an analgesic selected from the group consisting of paracetamol, non-steroidal anti-inflammatory drugs, and opioid drugs are preferred.
  • Tramadol hydrochloride is a centrally-acting analgesic, used in treating moderate to moderately severe pain. It is a synthetic analog of the phenanthrene alkaloid codeine and, as such, it is an opioid drug and also a pro-drug (codeine is metabolized to morphine in the body). Tramadol has a wide range of applications, including treatment for restless leg syndrome, acid reflux, and fibromyalgia. Tablets or capsules
  • a tablet is a pharmaceutical dosage form. It comprises a mixture of active
  • the compressed tablet is the most popular dosage form in use today. About two- thirds of all prescriptions are dispensed as solid dosage forms, and half of these are compressed tablets. A tablet can be formulated to deliver an accurate dosage to a specific site, and it is usually taken orally.
  • Medicinal tablets were originally made in the shape of a disk of whatever color their components determined, but are now made in many shapes and colors to help distinguish different medicines. Tablets are often embossed (or printed on outer coating) with symbols, letters, and numbers, which enable them to be identified.
  • the size of a tablet to be swallowed may range from a few millimeters to about a centimeter.
  • Some tablets are in the shape of capsules. Medicinal tablets and capsules are often called pills. This is technically incorrect, since tablets are made by compression, whereas pills are ancient solid dose forms prepared by rolling a soft mass into a round shape.
  • the tablets and the capsules are produced as known in the art.
  • the tablet or the capsule are for oral administration and comprises a) 0.5 - 50 % (w/w) hyaluronic acid or a salt thereof, b) an active pharmaceutical ingredient (API), and c) a coating.
  • API active pharmaceutical ingredient
  • the tablet or the capsule comprises 0.5 - 49 % (w/w) hyaluronic acid or a salt thereof, in particular the tablet or the capsule comprises 0.5 - 48 % (w/w) hyaluronic acid or a salt thereof, in particular the tablet or the capsule comprises 0.5 - 47 % (w/w) hyaluronic acid or a salt thereof, in particular the tablet or the capsule comprises 0.5 - 46 % (w/w) hyaluronic acid or a salt thereof, in particular the tablet or the capsule comprises 0.5 - 45 % (w/w) hyaluronic acid or a salt thereof, in particular the tablet or the capsule comprises 0.5 - 44 % (w/w) hyaluronic acid or a salt thereof, in particular the tablet or the capsule comprises 0.5 - 43 % (w/w) hyaluronic acid or a salt thereof, in particular the tablet or the capsule comprises 0.5 - 42 % (w/w)
  • the main guideline is to ensure that the appropriate amount of an active ingredient is placed in each tablet.
  • the ingredients should be well-mixed. If a sufficiently homogenous mix of the components cannot be obtained with simple blending processes, the ingredients may be, e.g., granulated prior to compression to assure an even distribution of the active compound in the final tablet.
  • Two basic techniques are used to granulate powders for compression into a tablet: wet granulation and dry granulation. Powders that can be mixed well do not require granulation and can be compressed into tablets through direct compression.
  • wet granulation is a process of using a liquid binder to lightly agglomerate the powder mixture.
  • the amount of liquid has to be properly controlled, as over-wetting will cause the granules to be too hard and under-wetting will cause them to be too soft and friable.
  • a typical procedure for wet granulation has the following steps:
  • Step 1 The active ingredient and excipient(s) are weighed and mixed.
  • Step 2 The wet granulate is prepared by adding the liquid binder/adhesive to the powder blend and mixing thoroughly.
  • binders/adhesives include aqueous preparations of corn starch, natural gums such as acacia, cellulose derivatives such as methyl cellulose, gelatin, and povidone.
  • Step 3 Sieving the damp mass through a mesh to form granules.
  • Step 4 Drying the granules.
  • a conventional tray-dryer or fluid-bed dryer are most commonly used.
  • Step 5 After the granules are dried, they are passed through a screen of smaller/uniform size than the one used for the wet mass in order to create granules of uniform size.
  • Low shear wet granulation processes use very simple mixing equipment, and can take a considerable time to achieve a uniformly mixed state.
  • High shear wet granulation processes use equipment that mixes the powder and liquid at a very fast rate, and thus speeds up the manufacturing process.
  • Fluid bed granulation is a multiple-step wet granulation process performed in the same vessel to pre-heat, granulate, and dry the powders. It is used because it allows close control of the granulation process.
  • Dry granulation processes create granules by light compaction of the powder blend under low pressures. The compacts so-formed are broken up gently to produce granules (agglomerates).
  • Dry granulation process is often used when the product to be granulated is sensitive to moisture and/or heat. Dry granulation can be conducted on a tablet press using slugging tooling or on a roll press called a roller compactor.
  • Dry granulation equipment offers a wide range of pressures to attain proper densification and granule formation. Dry granulation is simpler than wet granulation, therefore the cost is reduced. However, dry granulation often produces a higher percentage of fine granules, which can compromise the quality or create yield problems for the tablet.
  • Dry granulation requires drugs or excipients with cohesive properties, and a 'dry binder' may need to be added to the formulation to facilitate the formation of granules.
  • a final lubrication step is normally used to ensure that the tableting blend does not stick to the equipment during the tableting process. This usually involves low shear blending of the granules with a powdered lubricant, such as magnesium stearate, talcum, stearic acid or silicon dioxide.
  • a powdered lubricant such as magnesium stearate, talcum, stearic acid or silicon dioxide.
  • the additional excipients may include diluents, binders or granulating agents, glidants (flow aids) and lubricants to ensure efficient tabletting; disintegrants to promote tablet breakup in the digestive tract; sweeteners or flavours to enhance taste; and pigments to make the tablets visually attractive.
  • a preferred additional excipient is selected from the group consisting of a monosaccharide, a disaccharide, an oligosaccharide, a
  • polysaccharide polysaccharide, sugar alcohol, and talcum; in particular lactose, and cellulose, especially microcrystalline cellulose.
  • the tablet/capsule coatings must be stable and strong enough to survive the handling of the tablet/capsule, must not make tablets/capsules stick together during the coating process, and must follow the fine contours of embossed characters or logos on tablets.
  • a coating is also applied to make the tablet or the capsule smoother and easier to swallow, to control the release rate of the active ingredient, and/or to make the tablet or the capsule more resistant to the environment (e.g. gastric resistance). Tablet/capsule coatings are also useful to extend the shelf-life of components that are sensitive to moisture or oxidation.
  • the coating is especially applied in order to make the tablet or capsule more gastric resistant compared to a tablet or a capsule without a coating.
  • Gastric resistant or enteric resistant mean that the coating is resistant to stomach acid, but dissolves in the less acidic area of the intestines or colon.
  • the coating is a polymer.
  • the polymer has gastro resistant (acid resistant) properties.
  • the polymer is a cellulose derivate such as as a hypromelose or an acrylate, in particular methacrylic acid or methyl methacrylate.
  • Dissolution studies One way of showing that the active pharmaceutical compound is released slower in the digestive system/gastro intestinal tract - compared to a tablet or a capsule without the hyaluronic acid or the salt thereof - is by using dissolution studies.
  • Dissolution studies are a very used tool in the characterization of solid controlled release formulations. Dissolution is the process by which a solid, semi solid or liquid API enters into a solution in the presence of solvents.
  • Dissolution rate may be defined as the amount of active ingredient in a dosage form dissolved in unit per time under standardized conditions of agitation/flow, temperature, and media composition. The conditions used in standard testing are described both in European Pharmacopoeia (6.2) and USP (NF29 General Chapters ⁇ 71 1 > DISSOLUTION).
  • a tablet or a capsule according to the present invention may be for the manufacture of a medicament for the treatment of pain, migraine, epilepsy, anxious disorders, inflammatory conditions, infectious diseases, hormonal disorders, cardiovascular diseases, gastro intestinal illnesses or cancer.
  • Relevant illnesses and conditions are:
  • Inflammatory conditions acute and preventive treatment with and against steroids, NSAID's, rheumatism, psoriasis, osteoporosis and other autoimmune illnesses
  • the tablet or the capsule may particularly be a medicament for use in the treatment of pain according to the present invention.
  • the tablet or the capsule may particularly be a medicament for use in the treatment of migraine according to the present invention.
  • the tablet or the capsule may particularly be a medicament for use in the treatment of epilepsy according to the present invention.
  • the tablet or the capsule may particularly be a medicament for use in the treatment of an anxious disorder according to the present invention.
  • the tablet or the capsule may particularly be a medicament for use in the treatment of inflammatory conditions according to the present invention.
  • the tablet or the capsule may particularly be a medicament for use in the treatment of an infectious disease according to the present invention.
  • the tablet or the capsule may particularly be a medicament for use in the treatment of a hormonal disorder according to the present invention.
  • the tablet or the capsule may particularly be a medicament for use in the treatment of a cardiovascular disease according to the present invention.
  • the tablet or the capsule may particularly be a medicament for use in the treatment of a gastro intestinal illness according to the present invention.
  • the tablet or the capsule may particularly be a medicament for use in the treatment of cancer according to the present invention.
  • the tablet may be coated with an acid resistant coating.
  • the coating may consist of a methyl acrylate, methyl methacrylate and methacrylic acid (Eudragit® FS 30 D). This coating is insoluble in acidic media, but dissolves by salt formation above pH 7.0. It is a milky-white liquid of low viscosity with a faint characteristic odor in the aqueous dispersion of an anionic copolymer: Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid).
  • the coating may be performed in a fluid bed coater with top spray.
  • the coating layer on the dried tablets will consist of approx. 15 mg per tablet.
  • test system was based on the flow through system (USP Method 4): A flow- through cell (sample cell) where a test sample is placed in a specially designed cell through which media is pumped at a set and controlled temperature. The media is filtered upon leaving the cell and is then analyzed by UV. The type of cell is chosen to suit the dosage form, and it is permanently maintained at the set temperature (37°C) in a water jacket.
  • the dissolution system was prepared with the settings displayed in Table 3a, and every single cell was loaded with 1 tablet. Cell number 7 was blank and loaded with buffer.
  • Table 3a (Parameters and settings for the dissolution instrument)
  • a phosphate buffer pH 6.8 is used as dissolution media to simulate human intestinal fluids.
  • the tablet may be exposed to 0.1 M hydrochloric acid for up to 2 hours in the dissolution instrument. Afterwards the media may be changed to a 0.2 M Phosphate buffer at pH 7.8. This media change will happen automatically.
  • Table 3b Testing of gastro resistant tablets (Parameters and settings for the dissolution instrument)
  • Table 4 (Release times of tramadol hydrochloride from formulated tablets in 20 mM phosphate buffer)
  • the results show that the release time of the API increases with the HA concentration. For instance, 100% of the API is released after approx. 2.7 hours from tablets with 0.5% HA, and after approx.4.6 hours from tablets with 2.0% HA, while it takes approx. 6.7 hours to reach a 100% release from tablets with 4.0% HA.
  • the results show a prolonged release time of API when using increasing amounts of HA.
  • the release of 100 mg of tramadol hydrochloride from formulated tablets with HA in concentration from 0% to 4% is shown in Table 5.
  • the table illustrates that 100 % of the API is released after approx. 3.3 hours from tablets with 0.5% HA, after approx. 7.1 hours from tablets with 2.0% HA and after approx. 10.2 hours from tablets with 4.0% HA.
  • the results show a prolonged release time of API when using increasing amounts of HA.
  • the results show a prolonged release time of API when using 200 mM phosphate buffer instead of 20 mM phosphate buffer (approx. 10 hours compared of approx. 7 hours from tablets with 4.0% HA).
  • the tested formulations with HA from 0.5% to 2.0% can be characterized as medium slow release formulations because of the clear delay in API release.
  • the tested 4.0% HA formulation can be characterized as a slow release formulation.
  • the tablets containing HA were compared with commercial tablets (Tradolan ® and Nobligan ® ) in their performance to release tramadol hydrochloride (see Table 5). The complete release from Tradolan ® is observed after 0.6 hours and from Nobligan ® after approx 18.4 hours.
  • Example 1 HA is a slow release agent in a solid dose formulation.
  • 0.5-4.0 % HA in the formulated tablets has a very significant effect on the release profile of API (tramadol hydrochloride) compared to the tablet without HA. This indicates that the formulation can be changed from a medium release formulation to a slow release formulation by adding HA.
  • API tramadol hydrochloride

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP12751545.0A 2011-09-02 2012-08-31 Oral formulations containing hyaluronic acid for sustained drug release Withdrawn EP2750665A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP12751545.0A EP2750665A1 (en) 2011-09-02 2012-08-31 Oral formulations containing hyaluronic acid for sustained drug release

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP11179819 2011-09-02
PCT/EP2012/066975 WO2013030348A1 (en) 2011-09-02 2012-08-31 Oral formulations containing hyaluronic acid for sustained drug release
EP12751545.0A EP2750665A1 (en) 2011-09-02 2012-08-31 Oral formulations containing hyaluronic acid for sustained drug release

Publications (1)

Publication Number Publication Date
EP2750665A1 true EP2750665A1 (en) 2014-07-09

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EP12751545.0A Withdrawn EP2750665A1 (en) 2011-09-02 2012-08-31 Oral formulations containing hyaluronic acid for sustained drug release

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US (1) US20140302131A1 (enExample)
EP (1) EP2750665A1 (enExample)
KR (1) KR20140058581A (enExample)
CN (1) CN103781473A (enExample)
AU (1) AU2012300815A1 (enExample)
CA (1) CA2847328A1 (enExample)
IL (1) IL230787A0 (enExample)
IN (1) IN2014CN02343A (enExample)
WO (1) WO2013030348A1 (enExample)

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CN114767649A (zh) * 2021-12-22 2022-07-22 北京佗林医药科技有限公司 一种顺式透明质酸六糖的制剂及其制备方法
EP4487834A1 (en) 2023-07-07 2025-01-08 NuPep AS Consensus peptides in hya
EP4487863A1 (en) 2023-07-07 2025-01-08 NuPep AS Consensus peptides in hya for use in treating degenerated joints
EP4739277A1 (en) 2023-07-07 2026-05-13 NuPep AS Consensus peptides in hya

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IT1271001B (it) 1994-07-26 1997-05-26 Poli Ind Chimica Spa Procedimento di preparazione di acido ialuronico mediante fermentazione con streptococcus
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KR20140058581A (ko) 2014-05-14
CN103781473A (zh) 2014-05-07
IL230787A0 (en) 2014-03-31
AU2012300815A1 (en) 2014-02-20
CA2847328A1 (en) 2013-03-07
US20140302131A1 (en) 2014-10-09
WO2013030348A1 (en) 2013-03-07
IN2014CN02343A (enExample) 2015-06-19

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